1. Field of the Invention
The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula ##STR3## in which A represents a C.sub.1 -C.sub.6 straight or branched chain alkylene group; R.sup.5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical; and ##STR4## represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R.sup.5.
2. Description of the Prior Art
A number of .beta.-lactam derivatives containing the carbapenem nucleus ##STR5## have been disclosed in the literature. These carbapenem derivatives have been reported to possess utility as antibacterial agents and/or .beta.-lactamase inhibitors.
The initial carbapenem compounds were natural products such as thienamycin of the formula ##STR6## obtained by fermentation of Streptomyces cattleya (U.S. Pat. No. 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to .beta.-lactam antibiotics.
Other natural products containing the carbapenem nucleus include olivanic acid derivatives such as antibiotic MM 13902 of the formula ##STR7## disclosed in U.S. Pat. No. 4,113,856, antibiotic MM 17880 of the formula ##STR8## disclosed in U.S. Pat. No. 4,162,304, antibiotic MM 4550A of the formula ##STR9## disclosed in U.S. Pat. No. 4,172,129 and antibiotic 890A.sub.9 of the formula ##STR10## disclosed in U.S. Pat. No. 4,264,735. In addition to the natural products, the compound desacetyl 890A.sub.10 of the formula ##STR11## is disclosed in U.S. Pat. No. 4,264,734 as being prepared by an enzymatic deacylation of the corresponding N-acetyl compound. Various derivatives of the naturally-occuring olivanic acids have also been synthesized, e.g. the compounds of the formula ##STR12## wherein CO.sub.2 R.sub.1 is a free, salted or esterified carboxyl group, n is 0 or 1 and R.sub.2 is H, an acyl group or a group of the formula R.sub.3 O.sub.3 S wherein R.sub.3 is a salting ion or a methyl or ethyl group, disclosed in European Patent Application No. 8885.
U.S. Pat. No.4,235,922 (see also European Patent Application 2058) discloses the carbapenem derivative of the formula ##STR13## while U.K. Patent Application No. 1,598,062 reports isolation of the compound ##STR14## from a Streptomyces fermentation broth.
Carbapenems which are unsubstituted in the 6-position have also been synthesized. Thus, U.S. Pat. No. 4,210,661 discloses compounds of the formula ##STR15## wherein R.sub.2 is phenyl or substituted phenyl, U.S. Pat. No. 4,267,177 discloses compounds of the formula ##STR16## wherein R.sub.1 is an optionally substituted pyridyl group, U.S. Pat. No. 4,255,441 discloses compounds of the formula ##STR17## wherein R.sub.2 and R.sub.3 are H or alkyl and R.sub.4 is NH-CO.sub.n R.sub.6 in which R.sub.6 is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Pat. No. 4,282,236 discloses compounds of the formula ##STR18## wherein R.sub.1 is H or alkyl and R.sub.2 is CN or CO.sub.2 R.sub.3 in which R.sub.3 is H, alkyl, aryl or aralkyl.
Carbapenems of the general formula ##STR19## wherein R.sup.1 is H or acyl and R.sup.8 is H or substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclyalkyl, are disclosed in U.S. Pat. No. 4,218,463. There is no disclosure of any heteroaralkyl R.sup.8 substituents of the type ##STR20## in which A is alkylene and ##STR21## is a quaternized nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom.
The natural product thienamycin has the absolute configuration 5R, 6S, 8R. This isomer, as well as the remaining seven thienamycin isomers, may be obtained via total synthesis as disclosed in U.S. Pat. No. 4,234,596. Total synthesis procedures for thienamycin are also disclosed, for example, in U.S. Pat. Nos. 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,290,947 and European Patent Application No. 7973. A key intermediate in the disclosed synthetic methods is ##STR22## wherein pNB represents p-nitrobenzyl.
Because of the exceptional biological activity of thienamycin, a large number of derivatives have been prepared and disclosed in the literature. Among these are (1) N-formimidoyl thienamycin of the formula ##STR23## disclosed in European Patent Application No. 6639; (2) N-heterocyclic derivatives of thienamycin having the formula ##STR24## wherein: the bifunctional ring may contain additional unsaturation in the ring; and wherein n is an integer selected from 1-6; p is 0, 1 or 2; R.sup.1 is H, alkyl or aryl; and Z is imino, oxo, H, amino or alkyl, disclosed in U.S. Pat. No. 4,189,493; (3) substituted N-methylene derivatives of thienamycin having the formula ##STR25## wherein X and Y are H, R, OR, SR or NR.sup.1 R.sup.2 in which R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, and R.sup.1 and R.sup.2 are H or R, disclosed in U.S. Pat. No. 4,194,047; (4) compounds of the formula ##STR26## wherein R.sup.3 is aryl, alkyl, acyl or aralkyl and R.sup.1 and R.sup.2 are independently selected from H and acyl (including acyl of the type ##STR27## in which R.sup.11 may inter alia be alkyl substituted by a quaternary ammonium group, e.g. ##STR28## disclosed in U.S. Pat.No. 4,226,870; (5) compounds of the formula ##STR29## wherein R.sup.3 is H, acyl or an univalent optionally substituted hydrocarbon radical; R.sup.1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl and R.sup.2 is acyl (including acyl of the type ##STR30## in which R is alkyl substituted by a quaternary ammonium group, e.g. ##STR31## disclosed in U.K. Pat. No. 1,604,276 (see also U.S. Pat. No. 4,235,917); (6) compounds of the formula ##STR32## wherein R.sup.5, R.sup.6 and R.sup.7 are independently selected from H and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, are disclosed in U.S. Pat. No. 4,235,920; (7) compounds of the formula ##STR33## wherein each of R.sup.1 and R.sup.2, independently of the other, is a radical of the type defined for R, a hydrogen atom, or a nitro, hydroxyl, C.sub.1-6 alkoxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino or tri(C.sub.1-6 alkylamino) radical, an extra anion being present in the latter case; or R.sup.1 and R.sup.2 are joined together to form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl residue containing 4-10 ring atoms, one or more of which may be an additional hetero atom selected from oxygen, sulphur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (C.sub.1-10 alkoxy)carbonyl, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, C.sub.4-12 cycloalkylalkyl, C.sub.5-12 cycloalkylalkenyl, C.sub.3-10 cycloalkenyl, C.sub.5-12 cycloalkenylalkenyl, C.sub.4-12 cycloalkenylalkyl, C.sub.6-10 aryl, C.sub.7-16 aralkyl, C.sub.8-16 aralkenyl, C.sub.8-16 aralkynyl or monocyclic or bicyclic heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl comprising 4 to 10 ring atoms one or more of which is a hetero atom selected from oxygen, sulphur and nitrogen and in which the alkyl residue of the heteroaralkyl or heterocyclylalkyl radical contains from 1to 6 carbon atoms; the substituent or substituents on R, R.sup.1, R.sup.2 or on the ring formed by joining R.sup.1 and R.sup.2 are chlorine; bromine; iodine; fluorine; azido; C.sub.1-4 alkyl; mercapto; sulpho; phosphono; cyanothio (--SCN); nitro; cyano; amino; hydrazino; amino or hydrazino having up to three C.sub.1-6 alkyl substituents; hydroxy; C.sub.1-6 alkoxy; C.sub.1-6 alkylthio; carboxyl; oxo; (C.sub.1-6 alkoxy)carbonyl; C.sub.2-10 acyloxy; carbamoyl; (C.sub.1-4 alkyl)carbamoyl or di(C.sub.1-4 alkyl)carbamoyl; R.sub.3 is a hydrogen atom, an acyl radical or a radical of the type defined for R.sup.4 ; R.sup.4 is C.sub.1-10 alkyl; substituted carbonylmethyl; (C.sub.1-6 alkoxy)-(C.sub.1-6 alkyl), (C.sub.3-6 cycloalkoxy)(C.sub.1-6 alkyl); C.sub.2-12 alkanoyloxyalkyl; partially or completely halogenated C.sub.1-6 alkyl in which the halogen(s) is/are chlorine, bromine or fluorine; aminoalkyl; C.sub.2-10 alkenyl; C.sub.2-10 alkynyl; acyl; C.sub.3-14 alkoxycarbonylalkyl; C.sub.4-21 dialkylaminoacetoxyalkyl; C.sub.2-13 alkanoylaminoalkyl; ar-(C.sub.1-3 alkyl) in which the aryl residue contains from 6 to 10 carbon atoms; monocyclic or bicyclic heteroaralkyl or heterocyclylalkyl containing 4 to 10 ring atoms, 1 to 3 carbon atoms in the alkyl residue, and 1-4 hetero atoms selected from oxygen, sulphur and/or nitrogen; nuclear-substituted aralkyl or heteroaralkyl in which the substituent is chlorine, fluorine, bromine, iodine or C.sub.1-6 alkyl; aryl or nuclear-substituted aryl containing 6 to 10 ring carbon atoms and in which any nuclear substituent is hydroxy, C.sub.1-6 alkyl, chlorine, fluorine or bromine; aralkoxyalkyl; C.sub.2-12 alkylthioalkyl; C.sub.4-12 cycloalkylthioalkyl; (C.sub.2-10 acylthio)-(C.sub.1-6 alkyl); or phenylalkenyl in which alkenyl has 2-6 carbon atoms; R.sup.5 is substituted or unsubstituted C.sub.1-10 alkyl; C.sub.2-10 alkenyl or alkynyl; ring substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl having 3-6 ring carbon atoms and up to 6 carbon atoms in any chain; C.sub.6-10 aryl; aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; monocyclic or bicyclic heteroaryl or heteroaralkyl containing 4-10 ring atoms, one or more of which is oxygen, nitrogen or sulphur, and 1-6 carbon atoms in the alkyl chain; and the ring or chain substituent(s) is/are chlorine, bromine, iodine, fluorine, azido, cyano, amino, C.sub.1-6 alkylamino; di(C.sub.1-6 alkyl)amino or tri(C.sub.1-6 alkylamino) radical, an extra anion being present in the latter case, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylthioalkyl; carboxyl; oxo, (C.sub.1-6 alkoxy)carbonyl; C.sub.2-10 acyloxy; carbamoyl; (C.sub.1-4 alkyl)carbamoyl; di(C.sub.1-4 alkyl)carbamoyl; cyanothio (--SCN) or nitro; R.sup.6 is hydrogen, hydroxy, mercapto, R, --OR, --SR or NR.sup.1 R.sup.2, where R, R.sup.1 and R.sup.2 are as defined above; X is hydroxy, mercapto, amino, acyloxy --OR.sup.4, --SR.sup.4, --NHR.sup.4, ##STR34## --OM, OQ or, when the compound is in zwitterionic form, --O.sup.-, in which case A.sup.- is absent; A, when the compound is not in zwitterionic form, is a counter ion; M is a pharmaceutically acceptable cation; and Q is a blocking group as herein defined, are disclosed in U.K. Pat. No. 1,604,275; and (8) compounds of the formula ##STR35## wherein ##STR36## attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl, heterocyclylalkyl, aralkyl, --NR.sub.2, COOR, CONR.sub.2, --OR, or CN, are disclosed in European Patent Application No. 21082. Among the compounds disclosed in U.S. Pat. No. 4,235,920 is ##STR37## wherein A is a pharmaceutically acceptable anion. The above-mentioned quaternary amine derivative is also described in Recent Advances in the Chemistry of .beta.-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pg 240-254, where its antibacterial activity on average is reported as approximately 1/2 to 2/3 that of thienamycin.
Carbapenem derivatives having a wide variety of 6-substituents in addition to those mentioned above have also been synthesized. Thus, for example, (1) European Patent Application No. 40408 discloses compounds of the formula ##STR38## wherein R.sub.1 is H, methyl or hydroxyl and R.sub.51 is a monovalent organic group including inter alia heterocyclicalkyl; (2) European Patent Application No. 8514 discloses compounds of the formula ##STR39## wherein R.sub.1 is an optionally substituted pyrimidinyl group and R.sub.2 is hydrogen or a group CR.sub.3 R.sub.4 R.sub.5 wherein R.sub.3 is hydrogen or hydroxy, R.sub.4 is hydrogen or alkyl and R.sub.5 is hydrogen, alkyl, benzyl or phenyl, or R.sub.5 and R.sub.4 together form a carbocyclic ring; (3) European Patent Application No. 38869 discloses compounds of the formula ##STR40## wherein R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: ##STR41## wherein, relative to the above listed substituents on R.sup.6, R.sup.7, and R.sup.8, the groups R.sup.1 and R.sup.2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms. (See also European Patent Application Nos. 1627, 1628, 10317, 17992, 37080, 37081 and 37082); (4) European Patent Application No. 24832 discloses compounds of the formula ##STR42## wherein R.sup.1 is H or a group selected from OH, OSO.sub.3 H or a salt or C.sub.1-4 alkyl ester thereof, OR.sup.2, SR.sup.3, OCOR.sup.2, OCO.sub.2 R.sup.3 or OCONHR.sup.3, where R.sup.2 is a C.sub.1-6 alkyl group or an optionally substituted benzyl group and R.sup.3 is a C.sub.1-6 alkyl group or an optionally substituted benzyl or phenyl group and R.sup.12 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 alkynyl wherein the triple bond is not present on the carbon adjacent to the sulfur atom, aralkyl, C.sub.1-6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any of such R.sup.12 groups being optionally substituted, as antibacterial agents.
European Patent Application No. 44170 discloses carbapenem derivatives of the formula ##STR43## wherein R.sup.3 is hydrogen or an organic group bonded via a carbon atom to the carbapenem ring, n is 0 or 1, X is a saturated or unsaturated hydrocarbon radical optionally substituted by bromo or chloro, and R.sup.4 is a C.sub.1-6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.10 aralkyl or aryl group, any of such groups R.sup.4 being optionally substituted. There is no disclosure, however, of any compounds wherein the tetrazole ring is bonded to X via a quaternized nitrogen atom, i.e. a positively charged nitrogen which is not attached to a hydrogen atom.
European Patent Application No. 38,869 mentioned above discloses synthesis of the carbapenem derivatives via intermediates of the general formula ##STR44## wherein R.sup.6 and R.sup.7 are as defined above and R.sub.2 ' is a readily removable carboxyl protecting group. Also disclosed as intermediates are compounds of the formula ##STR45## wherein X is described as a leaving group.
At the Gordon Research Conference on Medicinal Chemistry held at New London, N.H. on Aug. 2-6, 1982, a handout was distributed in which a variety of carbapenem antibiotics were disclosed. Among the compounds disclosed on page 9 of the handout is the carbapenem of the formula ##STR46## which differs from the compounds of the present invention in that the quaternized heteroaromatic ring in the 2-substituent is bonded directly to the sulfur atom instead of to the carbon atom of an alkylene group.
European Patent Application No. 50,334 discloses carbapenem derivatives of the general formula ##STR47## wherein R.sup.6 and R.sup.7 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a direct, single bond connecting the indicated S and C atoms, or A is a cyclic or acyclic connecting group selected, inter alia, from alkyl, cycloalkyl, aryl, heteroaryl or heteroalkyl; R.sup.1 and R.sup.2, which define the carbamimidoyl function are, inter alia, independently selected from hydrogen, alkyl and aryl; additionally, said carbamimidoyl is characterized by cyclic structures achieved by the joinder of the two nitrogen atoms via their substituents and by their joinder to connecting group A; additionally "carbamimidiums" are disclosed by quaternization of one of the nitrogen atoms of said carbamimidoyl. On page 12 of this application, there is disclosed as a possible 2-substituent the group ##STR48## wherein R.sup.1 is defined as hydrogen, substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl and the two nitrogen atoms "participate in cyclic structures which are indicated by the dotted lines". No specific disclosure is provided of any cyclized carbamimidoyl groups containing a quaternized nitrogen atom, but page 22 does disclose a cyclized carbamimidoyl group of the formula ##STR49## Based on the indicated definitions of substituent R.sup.1, applicant does not believe that European Patent Application No. 50,334 generically discloses any of his compounds. However, since the language in the reference application is so vague as to the nature of the intended cyclic structures, applicant is making this reference of record in the present application.
While, as indicated above, the prior art has described carbapenem derivatives having a 2-substituent of the general formula EQU --S--A--Het
wherein A represents an alkylene group and Het represents a heterocyclic or heteroaromatic group, there has been no disclosure of which applicants are aware teaching carbapenems wherein Het is a radical of the formula ##STR50## in which R.sup.5 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclylaliphatic radical and ##STR51## represents a quaternized nitrogen-containing aromatic heterocycle bonded to the alkylene carbon via a ring carbon atom. As mentioned above, the carbapenem having ##STR52## as the 2-substituent has been reported as well as the carbapenem having a quaternized heteroaromatic ring bonded directly to the sulfur 2-substituent.
Despite the vast number of carbapenem derivatives disclosed in the literature, there is still a need for new carbapenems since known derivatives may be improved upon in terms of spectrum of activity, potency, stability and/or toxic side effects.